1. Field of the invention
The present invention relates to liquefied embolic materials capable of sol-gel phase transition in response to in vivo conditions, including temperature, ionic strength, and pH, and their uses. More particularly, the present invention relates to liquefied embolic materials made of copolymers which are based on temperature-sensitive isopropylacrylamide and ionic strength- and/or pH-sensitive monomers. Also, the present invention is concerned with pharmaceutically acceptable, embolic compositions comprising the embolic materials in liquid forms.
2. Description of the Prior Art
Embolotheraphy is a medical technique of closing dysfunctional blood vessels to normalize distorted blood flow or of obstructing the blood flow around lesions, especially cancers, to reduce sizes of the lesions (cancers), induce the withering of the disease entities to death, and simplify the operation for the removal of lesions with a minimal hemorrhage.
In order to embolize blood vessels, there have been developed a variety of embolic materials and devices, from among which the selection of appropriate ones is determined depending on the types, sizes and locations of target blood vessels. Generally, consisting of particulate synthetic polymers, human tissue fragments, or curable liquid materials, embolic materials are classified as xe2x80x9cdegradablexe2x80x9d and non-degradablexe2x80x9d depending on their biodegradability.
On the whole, a vascular embolic material must satisfy the following requirements: 1) that it completely embolize target blood vessels, 2) that it exhibit minimal toxicity with substantial absence of side effects to tissues around the locus where it is introduced, 3) that it cause minimal pain and be safe, 4) that it perform embolization with a high rate of success and prevent recurrence of blood flow, 5) that it allow convenience for the operation, 6) it be low in cost, and 7) it be applicable for blood vessels of various loci. Thus far, no vascular embolic materials have been reported which meet all the above requirements. For example, vascular embolic materials heretofore proposed are virtually impossible to apply for all types of embolization for various reasons, such as locations of blood vessels of interest, relevant organs, disease seriousness and so on.
For embolization, there have been developed a variety of types of means, including particulate materials and balloon devices. In recent times, liquid forms of embolic materials have been of special concern to those in the art for their ability to embolize fine blood vessels. Following are the materials suitable for use for this purpose.
Representative of the embolic materials which can be used in a liquid form at present, bucrylate, widely known as an instantaneous adhesive, is polymerized to a polymer by anion polymerization mechanism in the presence of water. In the medial field, this material is also used as an adhesive for tissues. Because of its rapid polymerization rate, bucrylate may be used in combination with glacial acetic acid to control its reaction rate when being used for embolization. However, this material suffers from the disadvantages of demanding a highly skilled expert in its application for embolization, owing to its polymerization being very difficult to control, and the requirement for use of an injection catheter which is specially designed not to be clogged by the material. What is worse, bucrylate may cause cancers in the body. Thus, it is recommended to use this putative carcinogenic material only for patients who are in critical condition. In addition, the biomedical effects of its biodegradation procedure and products of decomposition are highly controversial.
Silicon is injected, along with oligomers, crosslinking agents and catalysts, into blood vessels with the crosslinking rate being controlled by the mixture ratio of the components, as disclosed in U.S. Pat. No. No. 4,551,132. Advantages of the silicon material described in, this reference patent are its superb compatibility with blood without causing cancers. In addition, the silicon material is advantageous in that it is less toxic in vivo than other embolic materials and the length of time taken for coagulation in the blood vessel of a living body can be controlled within a wide range. However, the silicon material suffers from the drawback of being inconvenient for injection because of its high viscosity. Another drawback with the silicon material is that blood vessels, if small in diameter, cannot be selectively embolized by use of the silicon material.
Absolute ethanol damages endothelial cells of blood vessels and denaturates proteins of the tissues, giving rise to blood coagulation. With these advantages, this material is useful to embolize fine blood vessels. The use of absolute ethanol in embolization is usually accompanied by employing balloon catheters to prevent the backflow of enthanol. For this reason, absolute ethanol is difficult to apply for the embolization of cerebral vascular systems.
In recent times, there have been introduced thermosensitive polymers which are liquid at low temperatures but transform into solid forms at the body temperature. U.S. Pat. No. 5,525,334 discloses a method for vascular embolization of blood vessels, which takes advantage of this phase transition of such a thermosensitive polymer. In this method, an aqueous solution of a thermosensitive polymer is introduced into a blood vessel followed by in situ heating of the solution to cause coagulation. Because its phase transition is absolutely dependent on temperature, the material described in the reference patent, based fundamentally on isopropyl acrylamide, has the problem of clogging the catheter in use therewith as a result of the phase transition occurring within the catheter. Also, the thermosensitive embolic material cannot be transformed into a gel mass strong enough to withstand normal blood pressure, so that a complete vascular embolizing effect is not obtained.
Many other materials available for use in embolization have been developed. For example, U.S. Pat. No. 4,172,066 describes spheroidal microgels of a water-swollen or water-swellable, cross-linked polymer such as cross-linked polyacrylamide. In U.S. Pat. No. 4,358,355, there is described a polymeric material comprising acrylamide or derivatives thereof, acrylonitrile or derivatives thereof, acrylic acid and esters, or derivatives thereof, sulphonyl or phosphonyl derivatives, which can be used as components of gels. Another material is found in U.S. Pat. No. 4,732,930 which relates to an ionic gel formed by polymerization of isopropylacrylamide in the presence of an ion-containing monomer. This gel is capable of drastic volume change in response to external conditions. All of the gels described above, however, are problematic in that they cannot completely close blood vessels and may be leaked out of the blood vessels.
Therefore, it is an object of the present invention to overcome the above problems and disadvantages encountered in the prior art, such as inability to control the polymerization of monomers and to selectively embolize blood vessels of interest and clogging of injection catheters, and to provide a novel liquefied embolic material capable of sol-gel phase transition, which completely embolizes blood vessels of interest and prevents the recurrence of blood streaming in addition to being minimized in toxicity and side effects.
It is another object of the present invention to provide a pharmaceutical composition for embolizing blood vessels, which is based on the embolic material.
Because of its being converted to gel under a specific set of conditions defined by a temperature parameter, an ionic strength parameter and a pH parameter, the liquefied embolic material according to the present invention is free from clogging catheters by being gelled within catheters, unlike conventional materials sensitive only to temperature. Under the conditions which meet all the requirements for temperature, ionic strength and pH, the liquefied embolic material of the present invention is instantaneously converted into a solid form, thereby preventing itself from being released out of the lesion where it is injected.
In accordance with the present invention, the embolic material is a ready-polymerized polymeric mass which need not be further polymerized, so that polymerization of monomers does not occur within the human body. Additionally, no organic solvents are used upon the application of the embolic material; thus it avoids the side effects attributable to solvent leakage. Further, the embolic material can be applied to a broad spectrum of lesions, including solvent-sensitive loci.
Being non-degradable, the embolic material of the present invention can bring about the effect of preventing the recurrence of blood flow in the embolized blood vessel.
Constituting the embolic material of the present invention, synthetic copolymers can be made to have diverse molecular weights and viscosity properties by changing proportions of monomers and through different polymerization processes: embolic materials can be readily made suitable for use in the embolization of blood vessels of interest.
Over homopolymers consisting of, for example, isopropylacrylamide alone, the copolymers according to the present invention have the advantage in that they show high gel stability. When being used in combination with other particulate embolic materials, such as microspheres with a size of 0.1-100 xcexcm, each consisting of natural (proteins, polysaccharides, etc.) or synthetic polymers (PVA, PEG-PLLA) capable of encapsulating drugs of interest, and natural polymers helpful in stabilizing the gel, such as hyaluronic acid, carboxylated curdlan, pullulant and alginic acid, the embolic material exhibits better gel stability than when being used alone.
Superiority of the embolic material of the present invention to conventional ones can be proven in the field of histoengineering, which is directed to manufacture of artificial organs. To manufacture an artificial organ, a great number of cells are required, which are usually obtained by a three-dimensional culture process in which cells are fixed onto a matrix and cultured to a desired number, followed by the separation of the cultured cells from the matrix through spontaneous decomposition or compulsory removal of the matrix. The polymer prepared according to the present invention is useful as such a matrix. For example, the matrix made of the polymer of the present invention is maintained in a gel phase under a cell culture condition, e. g. at 37xc2x0 C. and returned to a sol phase when the temperature is lowered after completion of the culturing, segregating easily from the cells. On the other hand, the conventional polymer consisting mainly of isopropylamine cannot be converted at 37xc2x0 C. into gel hard enough to be used as a matrix for cell culture.
Also, the present invention finds an excellent application in the drug-delivery system for cancer therapy. As soon as they are administered in a conventional cancer therapy, anti-cancer drugs are diffused not only to perform their therapeutic functions against cancers, but also to cause various side-effects in normal cells. In contrast, as soon as it is administered into a cancer locus, in combination with anti-cancer drugs or an anti-cancer drug-carrying particle mixture of two types of particles with a size of 10-1000 nm and with a size of 1-1000 xcexcm, the polymer according to the present invention is converted into a hard gel in situ at the physiological condition (e. g., temperature) of the cancer to prevent the drugs from being diffused into other sites as well as from causing various side effects thereon. Additionally, the present invention can take advantage of physiological properties characteristic of cancer cells. For example, because cancer cells are of about pH 6.8, which is known to be lower than that of normal cells, the present invention can utilize a liquefied embolic material which is coagulated at the pH and temperature around caner cell loci, in delivering anti-cancer drug so as to prevent the diffusion of the drugs into other sites. Accordingly, the liquefied embolic material of the present invention can be applied for anti-cancer drug delivery systems.